ITFI950044A1 - BICYCLE COMPOUNDS, THEIR PREPARATION AND USE IN PHARMACEUTICAL COMPOSITIONS - Google Patents
BICYCLE COMPOUNDS, THEIR PREPARATION AND USE IN PHARMACEUTICAL COMPOSITIONS Download PDFInfo
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- ITFI950044A1 ITFI950044A1 IT95FI000044A ITFI950044A ITFI950044A1 IT FI950044 A1 ITFI950044 A1 IT FI950044A1 IT 95FI000044 A IT95FI000044 A IT 95FI000044A IT FI950044 A ITFI950044 A IT FI950044A IT FI950044 A1 ITFI950044 A1 IT FI950044A1
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- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000002446 fucosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)[C@@H](O1)C)* 0.000 description 1
- 125000002566 glucosaminyl group Chemical group 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
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- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 108010010478 neurokinin A(4-10) Proteins 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
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- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
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Abstract
La presente invenzione si riferisce a nuovi composti aventi formula generale: (FORMULA I) alla loro preparazione ed uso in composizioni farmaceutiche.The present invention relates to new compounds having general formula: (FORMULA I) to their preparation and use in pharmaceutical compositions.
Description
"Composti biciclici, loro preparazione ed uso in composizioni farmaceutiche" "Bicyclic compounds, their preparation and use in pharmaceutical compositions"
depositata il con il n° filed on with the no
Campo dell’invenzione Field of the invention
La presente invenzione si riferisce a nuovi composti aventi formula generale The present invention refers to new compounds having a general formula
(I) (THE)
ove : where:
che possono essere uguali o diversi tra loro, rappresentano un gruppo o un gruppo alchile; which can be the same or different from each other, represent an alkyl group or group;
Y rappresenta un gruppo preso fra Y represents a group caught between
cis o trans - ove R è H o un alchile; cis or trans - where R is H or an alkyl;
almeno uno dei gruppi uguali o diversi tra loro, è idrofilo ed i rimanenti gruppi sono idrofobi; at least one of the same or different groups is hydrophilic and the remaining groups are hydrophobic;
m ed n, uguali o diversi tra loro, sono ciascuno un numero intero da 1 a 4; m and n, equal to or different from each other, are each an integer from 1 to 4;
processi per la loro preparazione e composizioni farmaceutiche che li contengono. processes for their preparation and pharmaceutical compositions containing them.
Come si può vedere i composti di formula (I) come sopra descritti presentano centri chirali: resta inteso che i vari enantiomeri sono anch'essi oggetto della presente invenzione . As can be seen, the compounds of formula (I) as described above have chiral centers: it is understood that the various enantiomers are also the object of the present invention.
Stato dell’arte State of the art
Il recettore NK2 delle tachichinine è largamente espresso nel sistema nervoso periferico dei mammiferi. Uno dei vari effetti prodotti dalla stimolazione selettiva del recettore NK2 è la contrazione della muscolatura liscia. Quindi antagonisti del recettore NK2 possono essere considerati agenti capaci di controllare l'eccessiva contrazione della muscolatura liscia in ogni condizione patologica in cui il rilascio delle tachichinine concorre alla genesi del corrispondente disturbo. In particolare, la componente broncospastica dell'asma, della tosse, delle irritazioni polmonari e gli spasmi locali della vescica e dell'uretere durante cistiti, infezioni e coliche renali possono essere considerate condizioni in cui la somministrazione di antagonisti del recettore NK2 può essere efficace (A.L. Magnan et al. Neuropeptides, 1993, 24, 199). The tachykinin NK2 receptor is widely expressed in the mammalian peripheral nervous system. One of the various effects produced by selective stimulation of the NK2 receptor is the contraction of smooth muscle. Therefore NK2 receptor antagonists can be considered agents capable of controlling the excessive contraction of smooth muscle in any pathological condition in which the release of tachykinins contributes to the genesis of the corresponding disorder. In particular, the bronchospastic component of asthma, cough, pulmonary irritation and local spasms of the bladder and ureter during cystitis, infections and renal colic can be considered conditions in which the administration of NK2 receptor antagonists may be effective ( A.L. Magnan et al. Neuropeptides, 1993, 24, 199).
Composti antagonisti delle tachichinine, e in particolare della neurochinina A, sono noti in letteratura. Fra questi particolarmente interessanti sono i composti ciclici (B. J. Williams et al. J. Med. Chem. , 1993, 36, 2). La lipofilicità è stata definita un requisito essenziale per una elevata attività antagonista al recettore NK2 delle tachichinine di una serie di pseudopeptidi ciclici (L. Quartara et al. J. Med. Chem., 1994, 27) e particolarmente nel caso di esapeptidi biciclici (WO 93/21227). Sorprendentemente è stato ora trovato che prodotti strutturalmente analoghi a quelli sopra indicati ma in cui è invece presente almeno un gruppo idrofilo non solo mantengono l'elevata affinità in vitro, ma mostrano inoltre un incremento dell'attività farmacologica in vivo rispetto ai corrispondenti composti che non contengono gruppi idrofili . Antagonistic compounds of tachykinins, and in particular of neurokinin A, are known in the literature. Among these, cyclic compounds are particularly interesting (B. J. Williams et al. J. Med. Chem., 1993, 36, 2). Lipophilicity has been defined as an essential requirement for a high antagonist activity at the NK2 receptor of tachykinins of a series of cyclic pseudopeptides (L. Quartara et al. J. Med. Chem., 1994, 27) and particularly in the case of bicyclic hexapeptides ( WO 93/21227). Surprisingly it has now been found that products structurally similar to those indicated above but in which at least one hydrophilic group is instead present not only maintain the high affinity in vitro, but also show an increase in pharmacological activity in vivo compared to the corresponding compounds which do not contain hydrophilic groups.
Questo fatto è ancora più sorprendente quando si consideri che peptidi monociclici aventi analoghe proprietà di antagonismo delle tachichinine, non mostrano alcun incremento di attività quando gruppi idrofili vengono introdotti sulla struttura del ciclo [Int. J. Peptide Protein Res. (1984), 44:2, 105-111]. This fact is even more surprising when one considers that monocyclic peptides having similar antagonistic properties of tachykinins, do not show any increase in activity when hydrophilic groups are introduced on the structure of the cycle [Int. J. Peptide Protein Res. (1984), 44: 2, 105-111].
Descrizione dettagliata dell'invenzione Detailed description of the invention
La presente invenzione si riferisce a nuovi composti aventi formula generale (I) The present invention refers to new compounds having general formula (I)
(I) in cui i gruppi (I) in which groups
m ed n sono come sopra definiti; m and n are as defined above;
processi per la loro preparazione e composizioni farmaceutiche che li contengono. processes for their preparation and pharmaceutical compositions containing them.
Come si può vedere i composti di formula (I) come sopra descritti presentano centri chirali: resta inteso che i vari enantiomeri sono anch'essi oggetto della presente invenzione. As can be seen, the compounds of formula (I) as described above have chiral centers: it is understood that the various enantiomers are also the object of the present invention.
Più in particolare i gruppi idrofobi possono essere scelti separatamente fra i seguenti: More particularly, the hydrophobic groups can be selected separately from the following:
a) gruppi alchilici lineari o ramificati del tipo a) linear or branched alkyl groups of the type
con with
b) gruppi alchilici lineari o ramificati del tipo b) linear or branched alkyl groups of the type
con guanidino, with guanidino,
gruppo idrofobico contenente da 1 a 15 atomi di carbonio c) posti in una qualunque delle posizioni orto, meta o para, uguali o diversi tra loro, rappresentano H, alogeno, OR, NHR, NR2, ove R è un gruppo idrofobico con meno di 10 atomi di C hydrophobic group containing from 1 to 15 carbon atoms c) placed in any of the ortho, meta or para positions, equal to or different from each other, represent H, halogen, OR, NHR, NR2, where R is a hydrophobic group with less than 10 atoms of C
e) ove n = 0, 1-3 e per eterociclo si intende: imidazolil-2-il, indolil-3-il, furanil-3-il, piridil-3-il, imidazolil-3-il e) where n = 0, 1-3 and by heterocycle we mean: imidazolyl-2-yl, indolyl-3-yl, furanyl-3-yl, pyridyl-3-yl, imidazolyl-3-yl
f) un gruppo ove s=3, 4, eventualmente sostituito o condensato con un gruppo aromatico, che ciclizza con uno dei due gruppi X^_g adiacenti per dare la catena laterale di prolina, idrossiprolina, deidroprolina, acido ottaidroindol-2-carbossilico, acido tetraidroisochinolinico g) la catena laterale di un aminoacido naturale idrofobico h) la catena laterale di un aminocido naturale idrofilo opportunamente sostituita in modo da renderla idrofobica. i) la catena laterale di aminoacidi non naturali idrofobici scelti nel gruppo costituito da: norleucina, norvalina, alloisoleucina, cicloesilglicina (Chg), acido a-amino-nbutirrico (Aba), cicloesilalanina (Cha), acido aminofenilbutirrico (Pba), fenilalanine mono- e disostituite nelle posizioni orto, meta e para dell'anello benzenico con uno o più dei seguenti gruppi: alchile Cl-10, alcossi Cl-10, alogeno, β-2-tienilalanina, β-3-tienilalanina, β-2-furanilalanina, β-3-furanilalanina, β-2-piridilalanina, β-3-piridilalanina, β-4-piridilalanina, β-{1-naftil)alanina, fi-(2-naftil)alanina, derivati 0alchilati della aerina, treonina, tirosina, cisteina S-alchilata, omocisteina S-alchilata, lisina N-alchilata, ornitina N-alchilata, 2,3 diaminopropionico N-alchilato. Più in particolare la catena laterale di un aminoacido idrofobico secondo il punto (g) è la catena laterale di un aminoacido scelto nel gruppo costituito da: glieina, alanina, vaiina, leucina, isoleucina, metionina, fenilalanina, tirosina, triptofano, prolina, istidina. f) a group where s = 3, 4, possibly substituted or condensed with an aromatic group, which cyclizes with one of the two adjacent X ^ _g groups to give the side chain of proline, hydroxyproline, dehydroproline, octahydroindol-2-carboxylic acid, tetrahydroisoquinoline acid g) the side chain of a natural hydrophobic amino acid h) the side chain of a natural hydrophilic amino acid suitably substituted in order to make it hydrophobic. i) the side chain of non-natural hydrophobic amino acids selected from the group consisting of: norleucine, norvaline, alloisoleucine, cyclohexylglycine (Chg), a-amino-nbutyric acid (Aba), cyclohexylalanine (Cha), aminophenylbutyric acid (Pba), phenylalanine mono - and disubstituted in the ortho, meta and para positions of the benzene ring with one or more of the following groups: alkyl Cl-10, alkoxy Cl-10, halogen, β-2-thienylalanine, β-3-thienylalanine, β-2- furanylalanine, β-3-furanylalanine, β-2-pyridylalanine, β-3-pyridylalanine, β-4-pyridylalanine, β- {1-naphthyl) alanine, fi- (2-naphthyl) alanine, aerine 0alkylated derivatives, threonine , tyrosine, S-alkylated cysteine, S-alkylated homocysteine, N-alkylated lysine, N-alkylated ornithine, 2,3 N-alkylated diaminopropionic. More specifically, the side chain of a hydrophobic amino acid according to point (g) is the side chain of an amino acid chosen from the group consisting of: glieine, alanine, goine, leucine, isoleucine, methionine, phenylalanine, tyrosine, tryptophan, proline, histidine .
La catena laterale di un aminoacido idrofilo opportunamente sostituita in modo da renderla idrofobica secondo il punto (h) è la catena di un aminoacido scelto nel gruppo costituito da: serina, treonina, cisteina, acido aspartico, asparagina, acido glutammico, glutammina, acido tcarbossiglutammico, arginine, ornitina, lisina. The side chain of a hydrophilic amino acid suitably substituted so as to make it hydrophobic according to point (h) is the chain of an amino acid chosen from the group consisting of: serine, threonine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, tcarboxyglutamic acid , arginine, ornithine, lysine.
Preferibilmente i gruppi idrofili sono scelti nel gruppo L-Q, ove L è un legame chimico o un residuo alchilico lineare o ramificato c1-6 e Q è un gruppo idrofilo. Preferibilmente Q è scelto nel gruppo costituito da: guanidino, animino, M, OM, -CO-NH-M, -NH-CO-M, un gruppo aromatico mono, di o trisostituito in orto, meta, para con gruppi M o OM, ove M è un gruppo idrofilo. Preferably the hydrophilic groups are selected from the L-Q group, where L is a chemical bond or a linear or branched c1-6 alkyl residue and Q is a hydrophilic group. Preferably Q is selected from the group consisting of: guanidino, amino, M, OM, -CO-NH-M, -NH-CO-M, a mono, di or trisubstituted aromatic group in ortho, meta, para with M or OM groups , where M is a hydrophilic group.
Con il termine "gruppo idrofilo", per Q ed M, si intende preferibilmente: With the term "hydrophilic group", for Q and M, it is preferably meant:
i) residui mono-, di-, tri-glicosidici eventualmente sostituiti; i) mono-, di-, tri-glycosidic residues possibly substituted;
ii) catene alchiliche lineari o cicliche contenenti uno o più gruppi polari; ii) linear or cyclic alkyl chains containing one or more polar groups;
iii) ossidrile, ammino, guanidino, solfato, fosfonato, fosfato iii) hydroxyl, amino, guanidino, sulfate, phosphonate, phosphate
iv) residui portanti gruppi idrofili sostituiti che in ambiente biologico vengono idrolizzati ripristinando la funzione idrofila. iv) residues bearing substituted hydrophilic groups which are hydrolyzed in a biological environment restoring the hydrophilic function.
Con la definizione data al punto (i) qui sopra si intendono preferibilmente : The definition given in point (i) above preferably means:
esosi o pentosi della serie D o L nella configurazione a o β, scelti nel gruppo in cui: tutti gli atomi di C recano un gruppo ossidrilico, libero o protetto; uno o più degli ossidrili è sostituito da: idrogeno, un gruppo aminico o acilaminico; il Cg degli esosi e il C5 dei pentosi fa parte di un gruppo carbossilico; ed in cui le 2 o 3 unità glicosidiche eventualmente presenti sono unite attraverso un legame glicosidico di configurazione α o β. hexoses or pentoses of the D or L series in the a or β configuration, selected from the group in which: all the C atoms bear a free or protected hydroxyl group; one or more of the hydroxyls is replaced by: hydrogen, an amino or acylamine group; the Cg of the hexoses and the C5 of the pentoses are part of a carboxylic group; and in which the 2 or 3 glycosidic units possibly present are joined through a glycosidic bond of α or β configuration.
Specifici esempi dei gruppi glicosidici come sopra definiti sono: D o L ribosio, D o L arabinosio, D o L xilosio, D o L lixosio, D o L allosio, D o L altrosio, D o L glucosio, D o L mannosio, D o L gulosio, D o L idosio, D o L galattosio, D o L talosio, D o L allulosio, D o L fruttosio, D o L sorbosio, D o L tagatosio; 5-desossi-D o L-arabinosio , 2-desossi-D o L-glucosio, 2-desossi-D o L-galattosio , 2-desossi-D o L-arabinosio, 2-desossi-D o L-ribosio, D o L fucosio, D o L ramnosio; D-glucosamina, D-mannosamina, D-galattosamina, daunosamina, acosamina e loro derivati N-acilati con acidi grassi inferiori, cioè contenenti un residuo N-formilico, acetilico, propionilico, butirrilico; acido glucuronico, acido galatturonico; cellobiosio, lattosio, maltosio, D-lattosamina, cellotriosio, maltotriosio e loro derivati protetti. Con la definizione data al punto (ii) si intendono preferibilmente quelle derivanti dal residuo di un poliolo, quale tris(idrossimetil Jmetile, D o L arabitolo, D o L eritrolo, D o L galattitolo, meso-inositolo, D o L mannitolo, D o L perseitolo, D o L ribitolo, D o L sorbitolo, D o L xilitolo; oppure quelle derivanti dal residuo di acido tartarico, acido glucarico, acido gluconico, bicina, acido chinico, acido mucico, acido glucosaminico . Specific examples of the glycosidic groups as defined above are: D or L ribose, D or L arabinose, D or L xylose, D or L lixose, D or L allose, D or L altrose, D or L glucose, D or L mannose, D or L gulose, D or L idose, D or L galactose, D or L talose, D or L allulose, D or L fructose, D or L sorbose, D or L tagatose; 5-deoxy-D or L-arabinose, 2-deoxy-D or L-glucose, 2-deoxy-D or L-galactose, 2-deoxy-D or L-arabinose, 2-deoxy-D or L-ribose, D or L fucose, D or L rhamnose; D-glucosamine, D-mannosamine, D-galactosamine, daunosamine, acosamine and their N-acylated derivatives with lower fatty acids, i.e. containing an N-formyl, acetyl, propionyl, butyric residue; glucuronic acid, galacturonic acid; cellobiose, lactose, maltose, D-lactosamine, cellotriose, maltotriose and their protected derivatives. The definition given in point (ii) preferably means those deriving from the residue of a polyol, such as tris (hydroxymethyl Jmethyl, D or L arabitol, D or L erythritol, D or L galactitol, meso-inositol, D or L mannitol, D or L perseitol, D or L ribitol, D or L sorbitol, D or L xylitol; or those deriving from the residue of tartaric acid, glucaric acid, gluconic acid, bicine, quinic acid, mucic acid, glucosaminic acid.
Fra i prodotti di formula (I) come sopra indicati sono particolarmente preferiti i prodotti in cui se uno o entrambi i gruppi ed sono idrofili entrambi i gruppi 1*2 ed Rg sono idrofobi o viceversa. I composti di formula I) oggetto della presente invenzione possono essere sintetizzati con le varie tecniche note in letteratura, si veda ad esempio M. Bodansky, "Peptide Chemistry", Springer-Verlag, 1988. ;Ad esempio per sintesi in soluzione della catena peptidica lineare attraverso l’accoppiamento successivo di aminoacidi N-protetti opportunamente attivati ad un aminoacido o ad una catena peptidica C-protetta, con isolamento degli intermedi, successiva deprotezione selettiva delle catene C- ed N-terminali, ciclizzazione in solventi organici polari in soluzione diluita, indi deprotezione selettiva delle catene laterali e infine ciclizzazione fra le stesse in solventi organici polari in soluzione diluita. Il residuo idrofilo può essere introdotto sia come derivato aminoacidico protetto durante la sintesi della catena peptidica sia per coniugazione al peptide già formato, come ampiamente descritto in letteratura. ;Analogamente si può utilizzare per la preparazione una sintesi in fase solida della catena peptidica dalla estremità C-terminale verso quella N-terminale su di un supporto polimerico insolubile, la ciclizzazione in fase solida fra le catene laterali previamente deprotette, il successivo distacco dal supporto polimerico per idrolisi in acido fluoridrico anidro contenente gli opportuni scavengers o in acido trifluoroacetico contenente gli opportuni scavengers o in basi acquose e la ciclizzazione del peptide monociclico in solventi organici polari in soluzione diluita. Il residuo idrofilo essendo introdotto secondo le modalità sopra descritte. ;Secondo un particolare metodo di preparazione, il prodotto desiderato può essere ottenuto in fase solida adoperando la resina 2-clorotritile (Barlos et al., Int. J. Peptide Protein Res., 37, 513-520, 1991) sostituita con un aminoacido protetto con il gruppo Fmoc all'estremità N-terminale; preferibilmente 1*aminoacido direttamente legato alla resina è quello avente la catena laterale o R3. Dopo che gli altri aminoacidi sono stati introdotti nella sequenza, si distacca il peptide dalla resina con acido acetico diluito e si effettua una prima ciclizzazione fra le estremità C-terminale ed N-terminale libere mediante i classici metodi di sintesi. Successivamente si deproteggono le catene laterali degli aminoacidi in posizione 5 e 6, ad esempio con acido trifluoroacetico, e si procede alla seconda ciclizzazione. Among the products of formula (I) as indicated above, the products are particularly preferred in which if one or both groups and are hydrophilic both groups 1 * 2 and Rg are hydrophobic or vice versa. The compounds of formula I) object of the present invention can be synthesized with the various techniques known in the literature, see for example M. Bodansky, "Peptide Chemistry", Springer-Verlag, 1988.; For example by synthesis in solution of the peptide chain linear through the subsequent coupling of N-protected amino acids suitably activated to an amino acid or to a C-protected peptide chain, with isolation of the intermediates, subsequent selective deprotection of the C- and N-terminal chains, cyclization in polar organic solvents in dilute solution , selective deprotection of the side chains and finally cyclization between them in polar organic solvents in dilute solution. The hydrophilic residue can be introduced both as a protected amino acid derivative during the synthesis of the peptide chain and by conjugation to the already formed peptide, as widely described in the literature. Similarly, for the preparation it is possible to use a solid phase synthesis of the peptide chain from the C-terminal to the N-terminal end on an insoluble polymeric support, the solid phase cyclization between the previously deprotected side chains, the subsequent detachment from the support polymeric by hydrolysis in anhydrous hydrofluoric acid containing the appropriate scavengers or in trifluoroacetic acid containing the appropriate scavengers or in aqueous bases and the cyclization of the monocyclic peptide in polar organic solvents in dilute solution. The hydrophilic residue being introduced in the manner described above. ; According to a particular preparation method, the desired product can be obtained in solid phase using the 2-chlorotrityl resin (Barlos et al., Int. J. Peptide Protein Res., 37, 513-520, 1991) substituted with an amino acid protected with the Fmoc group at the N-terminal end; preferably the amino acid directly bound to the resin is the one having the side chain or R3. After the other amino acids have been introduced into the sequence, the peptide is detached from the resin with dilute acetic acid and a first cyclization is carried out between the free C-terminal and N-terminal ends by means of the classical synthesis methods. Subsequently, the side chains of the amino acids in position 5 and 6 are deprotected, for example with trifluoroacetic acid, and the second cyclization is carried out.
Altre vie sintetiche sono comunque possibili e largamente descritte in letteratura come suddetto. Other synthetic routes are however possible and widely described in the literature as above.
I composti di formula I) come sopra indicati si sono rivelati potenti antagonisti del recettore NK2 delle tachichinine, e quindi possono essere somministrati in dosi non inferiori rispetto a quelle richieste per i prodotti noti. The compounds of formula I) as indicated above have proved to be powerful antagonists of the NK2 receptor of tachykinins, and therefore can be administered in doses not lower than those required for the known products.
Possono quindi essere indicati per il trattamento di artrite, asma, infiammazioni, crescita tumorale, ipermotilità gastrointestinale, malattia di Huntington, neuriti, neuralgia, emicrania, ipertensione, incontinenza urinaria, orticaria, sintomi da sindrome carcinoide, influenza e raffreddori. They may therefore be indicated for the treatment of arthritis, asthma, inflammation, tumor growth, gastrointestinal hypermotility, Huntington's disease, neuritis, neuralgia, migraine, hypertension, urinary incontinence, urticaria, symptoms of carcinoid syndrome, flu and colds.
I composti di formula I) oggetto della presente invenzione, sono adatti per la somministrazione a fini terapeutici agli animali superiori ed all'uomo attraverso la via parenterale, orale, inalatoria e sublinguale raggiungendo effetti farmacologici in accordo con le proprietà sopra descritte. Per le vie parenterali (endovenosa, intramuscolare e intradermale) si impiegano soluzioni sterili o preparati liofilizzati. Per le vie di instillazione nasale, inalatoria e sublinguale si usano, a seconda del caso, soluzioni acquose, preparati aereosolici o capsule. The compounds of formula I) object of the present invention are suitable for administration for therapeutic purposes to higher animals and to man through the parenteral, oral, inhalation and sublingual routes, reaching pharmacological effects in accordance with the properties described above. For the parenteral routes (intravenous, intramuscular and intradermal) sterile solutions or lyophilized preparations are used. For the nasal, inhalation and sublingual instillation routes, aqueous solutions, aerosol preparations or capsules are used, depending on the case.
Le dosi di principio attivo nelle composizioni suddette possono essere comprese fra 0.1 e 10 mg/kg di peso corporeo. ESEMPIO 1 The doses of active principle in the above compositions can be comprised between 0.1 and 10 mg / kg of body weight. EXAMPLE 1
Preparazione di Preparation of
[composto di formula I) in cui: [compound of formula I) in which:
glucopiranosil); m = n = 1 e gli atomi di carbonio glucopyranosyl); m = n = 1 and the carbon atoms
hanno configurazione L]. have L configuration].
a) sintesi del peptide lineare a) synthesis of the linear peptide
1 g di resina 2-cloro tritile (1.6 mmol/g, NovaBiochem) viene funzionalizzato con Fmoc-Leu-OH (0.6 eq. ) come descritto da Barlos et al., Int. J. Peptide Protein Res., 1991, 37, 513-520. Il grado di sostituzione della resina viene determinato per dosaggio del gruppo Fmoc, e risulta di 0.364 meq/g. I successivi 4 aminoacidi vengono accoppiati come acidi liberi utilizzando un eccesso 3 di aminoacido e come attivanti HOBt (4 eg.) e DCC (3 eq.), con tempi di reazione di 1 h. Si aggiungono nell'ordine: Fmoc- 1 g of 2-chloro-trityl resin (1.6 mmol / g, NovaBiochem) is functionalized with Fmoc-Leu-OH (0.6 eq.) As described by Barlos et al., Int. J. Peptide Protein Res., 1991, 37, 513-520. The degree of resin substitution is determined by dosage of the Fmoc group, and is 0.364 meq / g. The following 4 amino acids are coupled as free acids using an excess 3 of amino acid and as activators HOBt (4 eg.) And DCC (3 eq.), With reaction times of 1 h. They are added in order: Fmoc-
L'ultimo aminoacido viene accoppiato The last amino acid is coupled
(Christiansen-Brams et al., J. Chem. Soc. Perkin Trans. I, 1993, 1461-1471), 2 eq., con attivante HOBt (2 eq.) per 3h. (Christiansen-Brams et al., J. Chem. Soc. Perkin Trans. I, 1993, 1461-1471), 2 eq., With HOBt activator (2 eq.) For 3h.
Dopo la deprotezione del gruppo Fmoc, si effettua il distacco dalla resina, sospendendola in 10 mL di una miscela di AcOH, TFE, DCM (1/1/8, v/v) a temp. amb. per 0.5 h. Indi si evapora il solvente sotto vuoto a 30°C, si riprende con acqua e si liofilizza. Resa in prodotto grezzo: 405 mg (90%). After deprotection of the Fmoc group, detachment from the resin is carried out, suspending it in 10 mL of a mixture of AcOH, TFE, DCM (1/1/8, v / v) at temp. amb. for 0.5 h. The solvent is then evaporated under vacuum at 30 ° C, taken up with water and lyophilized. Yield in crude product: 405 mg (90%).
14.7 min. 14.7 min.
b) Sintesi del prodotto biciclico b) Synthesis of the bicyclic product
(composto 2). (compound 2).
Il prodotto lineare grezzo viene ciclizzato in soluzione 1 mM in DMF, a 4°C, con 1 eq. di PyBOP e 1.2 eq. di DIEA per I h. La miscela viene portata a secco e purificata in HPLC ottenendo 156 mg di prodotto puro (resa 39%). Titolo HPLC: The crude linear product is cyclized in 1 mM solution in DMF, at 4 ° C, with 1 eq. of PyBOP and 1.2 eq. of DIEA for I h. The mixture is dried and purified in HPLC obtaining 156 mg of pure product (yield 39%). HPLC Title:
Il prodotto monociclico viene deprotetto sciogliendolo in 15 mL di TFA contenente il 10% di acqua. Dopo 0.5 h si diluisce la miscela con acqua e si liofilizza. Il residuo viene disciolto in soluzione 1 mM in DMF, la soluzione portata a 0°C e addizionata di 1 eq. di PyBOP e 1.2 eq di DIEA. Dopo 5 h si porta a secco e si purifica in HPLC. Resa 45% (70 mg). Titolo HPLC: >99%. FAB-MS: [M+H]+= 1074; tr: 13.5 min. The monocyclic product is deprotected by dissolving it in 15 mL of TFA containing 10% of water. After 0.5 h the mixture is diluted with water and lyophilized. The residue is dissolved in a 1 mM solution in DMF, the solution brought to 0 ° C and added with 1 eq. of PyBOP and 1.2 eq of DIEA. After 5 h it is dried and purified in HPLC. Yield 45% (70 mg). HPLC titer:> 99%. FAB-MS: [M + H] + = 1074; tr: 13.5 min.
c) Sintesi del prodotto biciclico c) Synthesis of the bicyclic product
70 mg di prodotto tetracetilato vengono disciolti in metanolo anidro in soluzione 5 mM. Si porta la soluzione a -20°C e si aggiunge una soluzione 1 M di metilato sodico in metanolo fino a raggiungere pH=ll. Dopo IO1 si aggiunge acido acetico fino a pH neutro, si diluisce fortemente con acqua e si liofilizza. Resa 60%. Titolo HPLC: 98%. FAB-MS: 70 mg of tetracetylated product are dissolved in anhydrous methanol in a 5 mM solution. The solution is brought to -20 ° C and a 1 M solution of sodium methylate in methanol is added until pH = 11 is reached. After 10 1 acetic acid is added up to neutral pH, diluted strongly with water and freeze-dried. Yield 60%. HPLC titer: 98%. FAB-MS:
[M+H]+= 906; tr: 9.3 min. [M + H] + = 906; tr: 9.3 min.
ESEMPIO 2 EXAMPLE 2
Preparazione di Preparation of
Leu]ciclo (2β-5β) } [composto di formula (I) in cui: Leu] cycle (2β-5β)} [compound of formula (I) where:
m = n = 1 e gli atomi di carbonio m = n = 1 and the carbon atoms
hanno configurazione L]. have L configuration].
a) sintesi del peptide lineare a) synthesis of the linear peptide
Si utilizza la procedura descritta per l'esempio 1), paragrafo a), fino all'aggiunta dell'ultimo aminoacido, che viene accoppiato come The procedure described for example 1), paragraph a) is used until the last amino acid is added, which is coupled as
(ottenuto con la procedura descritta da Vargas-Berenguel et al., J. Chem. Soc. Perkin Trans. I, 1994, 2615, 2619). (obtained with the procedure described by Vargas-Berenguel et al., J. Chem. Soc. Perkin Trans. I, 1994, 2615, 2619).
Il distacco avviene come descritto per l'esempio 1). Resa in prodotto grezzo: 450 mg (83%). Titolo HPLC: 93%. FAB-MS: The detachment takes place as described for example 1). Yield in crude product: 450 mg (83%). HPLC titer: 93%. FAB-MS:
[M+H]+= 1487; tr: 20.8 min. [M + H] + = 1487; tr: 20.8 min.
b) Sintesi del prodotto biciclico b) Synthesis of the bicyclic product
Il prodotto lineare grezzo viene ciclizzato in soluzione 1 mM in DMF, a 4°C, con 1 eq. di PyBOP e 1.2 eq. di DIEA per I h. La miscela viene portata a secco e purificata in HPLC ottenendo 0.16 g di prodotto puro (resa 35%). Titolo HPLC: tr: 25.3 min. The crude linear product is cyclized in 1 mM solution in DMF, at 4 ° C, with 1 eq. of PyBOP and 1.2 eq. of DIEA for I h. The mixture is dried and purified in HPLC obtaining 0.16 g of pure product (yield 35%). HPLC titer: tr: 25.3 min.
Il prodotto monociclico viene deprotetto sciogliendolo in 10 mL di TFA contenente il 10% di acqua. Dopo 0.5 h si diluisce la miscela con acqua e si liofilizza. Il residuo viene disciolto in soluzione 1 mM in DMF, la soluzione portata a 0°C e addizionata di 1 eq. di PyBOP e 1.2 eq di DIEA. Dopo 24 h si porta a secco e si purifica in HPLC. Resa 63 mg (45%). Titolo HPLC: >99%. FAB-MS: [M+H]+= 1295; tr: 21.6 min. The monocyclic product is deprotected by dissolving it in 10 mL of TFA containing 10% of water. After 0.5 h the mixture is diluted with water and lyophilized. The residue is dissolved in a 1 mM solution in DMF, the solution brought to 0 ° C and added with 1 eq. of PyBOP and 1.2 eq of DIEA. After 24 h it is dried and purified in HPLC. Yield 63 mg (45%). HPLC titer:> 99%. FAB-MS: [M + H] + = 1295; tr: 21.6 min.
c) Sintesi del prodotto biciclico c) Synthesis of the bicyclic product
Trp-Phe-Dap-Leu] ciclo(2β-5β) }. Trp-Phe-Dap-Leu] cycle (2β-5β)}.
20 mg di prodotto tetrabenzoilato vengono disciolti in metanolo anidro in soluzione 5 mH. Si porta la soluzione a -20°C e si aggiunge una soluzione 1 M di inetilato sodico in metanolo fino a raggiungere pH=ll. Dopo 1.5 h si aggiunge acido acetico fino a pH neutro, si diluisce fortemente con acqua e si liofilizza. 20 mg of tetrabenzoylated product are dissolved in anhydrous methanol in a 5 mH solution. The solution is brought to -20 ° C and a 1 M solution of sodium inethylate in methanol is added until pH = 11 is reached. After 1.5 h acetic acid is added up to neutral pH, diluted strongly with water and freeze-dried.
Procedendo in modo analogo si sono ottenuti i seguenti composti : Proceeding in a similar way, the following compounds were obtained:
ESEMPIO 3 EXAMPLE 3
[composto di formula I) in cui: [compound of formula I) in which:
glucopiranosil ). e gli altri sostituenti sono come definiti nell'esempio 1] ESEMPIO 4 glucopyranosyl). and the other substituents are as defined in Example 1] EXAMPLE 4
ciclo {[Asn(β-D-glucosaminil ) cycle {[Asn (β-D-glucosaminyl)
5β)} [composto di formula I) 4 2 5β)} [compound of formula I) 4 2
glucosaminil ) e gli altri sostituenti sono come definiti nell'esempio 1]. glucosaminil) and the other substituents are as defined in Example 1].
ESEMPIO 5 EXAMPLE 5
ciclo{ [Asn(2-N-acetil-fi-D-glucosaminil ) cycle {[Asn (2-N-acetyl-fi-D-glucosaminyl)
ciclo (2β-5β)} [composto di formula I) in cui R cycle (2β-5β)} [compound of formula I) where R
NH-[(2-N-acetil)fi-D-glucosaminil] e gli altri sostituenti sono come definiti nell’esempio 1]. NH - [(2-N-acetyl) fi-D-glucosaminyl] and the other substituents are as defined in example 1].
ESEMPIO 6 EXAMPLE 6
ciclo{[Nle-Asp-Trp-Phe-Dap-Asn(2-N-acetil-D-D-glucosaminil)] ciclo(2β-5β)} [composto di formula I) in cui {[Nle-Asp-Trp-Phe-Dap-Asn (2-N-acetyl-D-D-glucosaminyl)] cycle (2β-5β)} [compound of formula I) in which
NH-[(2-N-acetil)fi-D-glucosaminil] e gli altri sostituenti sono come definiti nell'esempio 3]. NH - [(2-N-acetyl) fi-D-glucosaminyl] and the other substituents are as defined in Example 3].
ESEMPIO 7 EXAMPLE 7
ciclo{[Asn(β-D-ribofuranosil)-Asp-Trp-Phe-Dap-Leu]ciclo(2β-5β)} [composto di formula I) in cui cycle {[Asn (β-D-ribofuranosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) in which
ribofuranosil) e gli altri sostituenti sono come definiti nell'esempio 1]. ribofuranosyl) and the other substituents are as defined in Example 1].
ESEMPIO 8 EXAMPLE 8
ciclo{[Nle-Asp-Trp-Phe-Dap-Asn(β-D-ribofuranosil)]ciclo(2β-5β)} [composto di formula I) in cui R^= {[Nle-Asp-Trp-Phe-Dap-Asn (β-D-ribofuranosyl)] cycle (2β-5β)} [compound of formula I) where R ^ =
ribofuranosil) e gli altri sostituenti sono come definiti nell'esempio 3] ribofuranosil) and the other substituents are as defined in Example 3]
ESEMPIO 9 EXAMPLE 9
ciclo{[Ser(β-D-ribofuranosil)-Asp-Trp-Phe-Dap-Leu]ciclo(2β-5β)} [composto di formula I) in cui {[Ser (β-D-ribofuranosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) where
ribofuranosil), e gli altri sostituenti sono come definiti nell’esempio 1] ribofuranosil), and the other substituents are as defined in example 1]
ESEMPIO 10 EXAMPLE 10
ciclo{[Asn(β-L-arabinofuranosil)-Asp-Trp-Phe-Dap-Leu]ciclo [composto di formula I) in cui R4= 2 L-arabinofuranosil ) e gli altri sostituenti sono come definiti nell'esempio 1] cycle {[Asn (β-L-arabinofuranosyl) -Asp-Trp-Phe-Dap-Leu] cycle [compound of formula I) in which R4 = 2 L-arabinofuranosyl) and the other substituents are as defined in example 1]
ESEMPIO 11 EXAMPLE 11
ciclo {[Nle-Asp-Trp-Phe-Dap-Asn(fì-L-arabinofuranosil) ]ciclo (2β-5β )} [composto di formula I) in cui R1= {[Nle-Asp-Trp-Phe-Dap-Asn (fì-L-arabinofuranosil)] cycle (2β-5β)} [compound of formula I) where R1 =
L-arabinofuranosil ) e gli altri sostituenti sono come definiti nell'esempio 3]. L-arabinofuranosyl) and the other substituents are as defined in Example 3].
ESEMPIO 12 EXAMPLE 12
ciclo{ [Ser(β-L-arabinofuranosil )-Asp-Trp-Phe-Dap-Leu] ciclo (2β-5β)} [composto di formula I) in cui {[Ser (β-L-arabinofuranosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) where
arabinof uranosil ) e gli altri sostituenti sono come definiti nell'esempio 1]. arabinof uranosyl) and the other substituents are as defined in Example 1].
ESEMPIO 13 EXAMPLE 13
ciclof [Asn(fi-D-mannopiranosil )-Asp-Trp-Phe-Dap-Leu] ciclo (2β -5β) } [composto di formula I) in cui cyclof [Asn (fi-D-mannopyranosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β -5β)} [compound of formula I) in which
mannopiranosil) e gli altri sostituenti sono come definiti nell 'esempio 1]. mannopyranosil) and the other substituents are as defined in Example 1].
ESEMPIO 14 EXAMPLE 14
ciclo {[Nle-Asp-Trp-Phe-Dap-Asn (β-D-mannopiranosil )]ciclo (2B —5β)} [composto di formula I) in cui {[Nle-Asp-Trp-Phe-Dap-Asn (β-D-mannopyranosyl)] cycle (2B -5β)} [compound of formula I) where
mannopiranosil ) e gli altri sostituenti sono come definiti nell'esempio 3] mannopyranosil) and the other substituents are as defined in Example 3]
ESEMPIO 15 EXAMPLE 15
ciclo {[Ser(β-D-mannopiranosil )-Asp-Trp-Phe-Dap-Leu] eie lo(2β -5β )} [composto di formula I) in cui: 4 2 mannopiranosil), e gli altri sostituenti sono come definiti nell'esempio 1] cycle {[Ser (β-D-mannopyranosyl) -Asp-Trp-Phe-Dap-Leu] eie lo (2β -5β)} [compound of formula I) where: 4 2 mannopyranosyl), and the other substituents are as defined in example 1]
ESEMPIO 16 EXAMPLE 16
ciclo{[Asn(β-D-galattopiranosil )-Asp-Trp-Phe-Dap-Leu]ciclo (2β-5β)} [composto di formula I) in cui cycle {[Asn (β-D-galactopyranosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) in which
D-galattopiranosil ) e gli altri sostituenti sono come definiti nell’esempio 1]. D-galactopyranosil) and the other substituents are as defined in example 1].
ESEMPIO 17 EXAMPLE 17
ciclo{[Nle-Asp-Trp-Phe-Dap-Asn(fi-D-galattopiranosil)]ciclo (2β-5β)} [composto di formula I) in cui {[Nle-Asp-Trp-Phe-Dap-Asn (fi-D-galactopyranosyl)] cycle (2β-5β)} [compound of formula I) where
galattopiranosil ) e gli altri sostituenti sono come definiti nell'esempio 3]. galactopyranosyl) and the other substituents are as defined in Example 3].
ESEMPIO 18 EXAMPLE 18
ciclo{[Ser(β-D-mannopiranosil )-Asp-Trp-Phe-Dap-Leu]ciclo(2β -5fi)} [composto di formula I) in cui {[Ser (β-D-mannopyranosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β -5fi)} [compound of formula I) where
galattopiranosil ) e gli altri sostituenti sono come definiti nell'esempio 1]. galactopyranosyl) and the other substituents are as defined in Example 1].
ESEMPIO 19 EXAMPLE 19
ciclo{[Asn(β-D-glucuronopiranosil )-Asp-Trp-Phe-Dap-Leu]ciclo (2β-5β)} [composto di formula I) in cui {[Asn (β-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) in which
glucuronopiranosil ) e gli altri sostituenti sono come definiti nell’esempio 3]. glucuronopyranosyl) and the other substituents are as defined in example 3].
ESEMPIO 20 EXAMPLE 20
ciclo{[Nle-Asp-Trp-Phe-Dap-Asn(fì-D-glucuronopiranosil)]ciclo (2β-5β)} [composto di formula I) in cui {[Nle-Asp-Trp-Phe-Dap-Asn (fì-D-glucuronopyranosyl)] cycle (2β-5β)} [compound of formula I) in which
D-glucuronopiranosil) e gli altri sostituenti sono come definiti nell’esempio 3]. D-glucuronopyranosyl) and the other substituents are as defined in example 3].
ESEMPIO 21 EXAMPLE 21
ciclo{[Ser(β-D-glucuronopiranosil)-Asp-Trp-Phe-Dap-Leu ]ciclo (2β-5β)} [composto di formula I) in cui {[Ser (β-D-glucuronopyranosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) where
glucuronopiranosil) e gli altri sostituenti sono come definiti nell'esempio 1]. glucuronopyranosyl) and the other substituents are as defined in Example 1].
ESEMPIO 22 EXAMPLE 22
ciclo{[Asn(1-desossi-sorbitol-l-il)-Asp-Trp-Phe-Dap-Leu] ciclo(2β-5β)} [composto di formula I) in cui cycle {[Asn (1-deoxy-sorbitol-1-yl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) in which
NH—(1—desossi—sorbitol—1—il) e gli altri sostituenti sono come definiti nell’esempio 3]. NH— (1 — deoxy — sorbitol — 1 — il) and the other substituents are as defined in example 3].
ESEMPIO 23 EXAMPLE 23
ciclo{[Nle-Asp-Trp-Phe-Dap-Asn(1-desossi-sorbitol-l-il )] ciclo(2β-5β)} [composto di formula I) in cui R {[Nle-Asp-Trp-Phe-Dap-Asn (1-deoxy-sorbitol-1-yl)] cycle (2β-5β)} [compound of formula I) where R
NH-(1-desossi-sorbitol-l-il) e gli altri sostituenti sono come definiti nell'esempio 3] NH- (1-deoxy-sorbitol-1-yl) and the other substituents are as defined in Example 3]
ESEMPIO 24 EXAMPLE 24
ciclo{[Asn[(β-D-glucopiranosil)-β-D-glucopiranosil]-Asp-Trp -Phe-Dap-Leu]ciclo{2β-5β)} [composto di formula I) in cui (b-D-glucopiranosil)-B-D-glucopiranosil) e gli altri sostituenti sono come definiti nell'esempio 1] ESEMPIO 25 {[Asn [(β-D-glucopyranosyl) -β-D-glucopyranosyl] -Asp-Trp -Phe-Dap-Leu] cycle {2β-5β)} [compound of formula I) wherein (b-D-glucopyranosyl) -B-D-glucopyranosyl) and the other substituents are as defined in Example 1] EXAMPLE 25
ciclo{[Nle-Asp-Trp-Phe-Dap-[(β-D-glucopiranosil)-β-D-gluco piranosil]]ciclo(2β-5β)} [composto di formula I) in cui R^= (fì-D-glucopiranosil)-3-D-glucopiranosil) e gli altri sostituenti sono come definiti nell'esempio 3]. {[Nle-Asp-Trp-Phe-Dap - [(β-D-glucopyranosyl) -β-D-gluco pyranosyl]] cycle (2β-5β)} [compound of formula I) where R ^ = (fì -D-glucopyranosyl) -3-D-glucopyranosyl) and the other substituents are as defined in Example 3].
ESEMPIO 26 EXAMPLE 26
ciclo{ [Asn[(β-D-galattopiranosil)-β-D-glucopiranosil]-Asp-Trp -Phe-Dap-Leu ]ciclo(2β-5β)} [composto di formula I) in cui (β-D-galattopiranosil)-β-D-glucopiranosil)e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 27 {[Asn [(β-D-galactopyranosyl) -β-D-glucopyranosyl] -Asp-Trp -Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) in which (β-D- galactopyranosyl) -β-D-glucopyranosyl) and the other substituents are as defined in Example 1]. EXAMPLE 27
ciclo {[Nle-Asp-Trp-Phe-Dap-Asn[(β-D-galattopiranosil)-5-D-glucopiranosil ]]ciclo(2β-5β)} [composto di formula I) in cui [(β-D-galattopiranosil)-β-D-glucopiranosil)e gli altri sostituenti sono come definiti nell'esempio 3]. ESEMPIO 28 {[Nle-Asp-Trp-Phe-Dap-Asn [(β-D-galactopyranosyl) -5-D-glucopyranosyl]] cycle (2β-5β)} [compound of formula I) where [(β-D -galattopiranosil) -β-D-glucopyranosyl) and the other substituents are as defined in Example 3]. EXAMPLE 28
ciclo {[Asn[Ο-α-D-glucopiranosil- j j glucopiranosil ^ j -α-D-glucopiranosi1]- cycle {[Asn [Ο-α-D-glucopyranosyl- j j glucopyranosil ^ j -α-D-glucopyranosis1] -
-5β)} [composto di formula I) in cui: -5β)} [compound of formula I) where:
D-glucopiranosil glucopiranosil- D-glucopyranosyl glucopyranosyl-
glucopiranosil ) e gli altri sostituenti sono come definiti nell'esempio 1]. glucopyranosyl) and the other substituents are as defined in Example 1].
ESEMPIO 29 EXAMPLE 29
ciclo {[Nle-Asp-Trp-Phe-Dap-Asn[Ο-α-D-glucopiranosil-( ]4)- glucopiranosil- -glucopiranosil]]ciclo(2β-5fi)} [composto di formula I) in cui cycle {[Nle-Asp-Trp-Phe-Dap-Asn [Ο-α-D-glucopyranosyl- (] 4) - glucopyranosyl- -glucopyranosyl]] cycle (2β-5fi)} [compound of formula I) in which
glucopiranosil- glucopiranosil j j glucopiranosil ) e gli altri sostituenti sono come definiti nell'esempio 3]. glucopyranosyl-glucopyranosyl j glucopyranosyl) and the other substituents are as defined in Example 3].
ESEMPIO 30 EXAMPLE 30
ciclo {[Asp(D-glucosaminil )-Asp-Trp-Phe-Dap-Leu ]ciclo (2β-5β)} [composto di formula I) in cui glucosaminil ) e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 31 cycle {[Asp (D-glucosaminyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) in which glucosaminyl) and the other substituents are as defined in Example 1]. EXAMPLE 31
ciclo{ [Nle-Asp-Trp-Phe-Dap-Asp( D-glucosaminil )]ciclo(2fi-5fi)} [composto di formula I) in cui (D-glucosaminil ) e gli altri sostituenti sono come definiti nell'esempio 3]. ESEMPIO 32 cycle {[Nle-Asp-Trp-Phe-Dap-Asp (D-glucosaminyl)] cycle (2fi-5fi)} [compound of formula I) in which (D-glucosaminyl) and the other substituents are as defined in the example 3]. EXAMPLE 32
ciclo{ [Dap[D(-)-chinil ]-Asp-Trp-Phe-Dap-Leu] ciclo( 2β-5β) } [composto di formula I) in cui: chinil] , e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 33 cycle {[Dap [D (-) - quinyl] -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) in which: quinyl], and the other substituents are as defined in example 1]. EXAMPLE 33
ciclo{ [Nle-Asp-Trp-Phe-Dap-Dap[D(-)-chinil ]ciclo(2β-5β) } [composto di formula I) in cui chinil) e gli altri sostituenti sono come definiti nell'esempio 3]. ESEMPIO 34 cycle {[Nle-Asp-Trp-Phe-Dap-Dap [D (-) - quinyl] cycle (2β-5β)} [compound of formula I) wherein quinyl) and the other substituents are as defined in Example 3 ]. EXAMPLE 34
ciclo{ [Dap[D-gluconil ]- ciclo (2β-5β)} [composto di formula I) in cui: -gluconil ) e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 35 cycle {[Dap [D-gluconyl] - cycle (2β-5β)} [compound of formula I) in which: -gluconyl) and the other substituents are as defined in Example 1]. EXAMPLE 35
ciclo {[Nle-Asp-Trp-Phe-Dap-Dap [D-gluconil ]ciclo cycle {[Nle-Asp-Trp-Phe-Dap-Dap [D-gluconyl] cycle
[composto di formula I) in cui gluconil ) e gli altri sostituenti sono come definiti nell'esempio 3]. [compound of formula I) wherein gluconyl) and the other substituents are as defined in Example 3].
ESEMPIO 36 EXAMPLE 36
ciclo{[Dap[D-glucuril ] cycle {[Dap [D-glucuril]
[composto di formula I) in cui e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 37 [compound of formula I) wherein and the other substituents are as defined in Example 1]. EXAMPLE 37
ciclo{[Nle-Asp-Trp-Phe-Dap-Dap [D-glucuril]ciclo(2β- 5β)} [composto di formula I) in cui cycle {[Nle-Asp-Trp-Phe-Dap-Dap [D-glucuril] cycle (2β- 5β)} [compound of formula I) in which
glucuril) e gli altri sostituenti sono come definiti nell'esempio 3]. glucuril) and the other substituents are as defined in Example 3].
ESEMPIO 38 EXAMPLE 38
ciclo{[Dap (2-solfo-benzoil)-Asp-Trp-Phe-Dap-Leu]ciclo(2β-5β )} [composto di formula I) in cui: cycle {[Dap (2-sulfo-benzoyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) where:
e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 39 and the other substituents are as defined in Example 1]. EXAMPLE 39
ciclo{[Nle-Asp-Trp-Phe-Dap-Dap(2-solfo-benzoil )]ciclo{2β-5β)} [composto di formula I) in cui e gli altri sostituenti sono come definiti nell'esempio 3]. cycle {[Nle-Asp-Trp-Phe-Dap-Dap (2-sulfo-benzoyl)] cycle {2β-5β)} [compound of formula I) in which and the other substituents are as defined in Example 3].
ESEMPIO 40 EXAMPLE 40
ciclo{[Asn(4-solfo-fenil )-Asp-Trp-Phe-Dap-Leu]ciclo(2β-5β)} [composto di formula I) in cui: cycle {[Asn (4-sulfo-phenyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) where:
e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 41 and the other substituents are as defined in Example 1]. EXAMPLE 41
ciclo{[Nle-Asp-Trp-Phe-Dap-Asn(4-solfo-fenil )]ciclo{2β-5β)} [composto di formula I) in cui cycle {[Nle-Asp-Trp-Phe-Dap-Asn (4-sulfo-phenyl)] cycle {2β-5β)} [compound of formula I) in which
e gli altri sostituenti sono come definiti nell'esempio 3]. and the other substituents are as defined in Example 3].
ESEMPIO 42 EXAMPLE 42
ciclo {[Asn(β-L-glucosil )-Asp-Trp-Phe-Dap-Leu ]ciclo(2β-5β ) [composto di formula I) in cui -glucosil ) e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 43 cycle {[Asn (β-L-glucosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β) [compound of formula I) in which -glucosyl) and the other substituents are as defined in Example 1 ]. EXAMPLE 43
ciclo{ [Nle-Asp-Trp-Phe-Dap-Asn(B-L-glucosil )]ciclo(2β-5β) } [composto di formula I) in cui cycle {[Nle-Asp-Trp-Phe-Dap-Asn (B-L-glucosyl)] cycle (2β-5β)} [compound of formula I) in which
glucosil) e gli altri sostituenti sono come definiti nell'esempio 3]. glucosyl) and the other substituents are as defined in Example 3].
ESEMPIO 44 EXAMPLE 44
ciclo {[Asn(β-L-f ucosil )-Asp-Trp-Phe-Dap-Leu ]ciclo(2β-5β) } [composto di formula I) in cui 4 2 (β-L-f ucosil ) e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 45 cycle {[Asn (β-L-f ucosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2β-5β)} [compound of formula I) in which 4 2 (β-L-f ucosyl) and the other substituents are as defined in example 1]. EXAMPLE 45
ciclo{ [Nle-Asp-Trp-Phe-Dap-Asn(fl-L-f ucosil) ]ciclo(2β-5β )} [composto di formula I) in cui cycle {[Nle-Asp-Trp-Phe-Dap-Asn (fl-L-f ucosil)] cycle (2β-5β)} [compound of formula I) in which
fucosil ) e gli altri sostituenti sono come definiti nell'esempio 3]. fucosil) and the other substituents are as defined in Example 3].
ESEMPIO 46 EXAMPLE 46
ciclo{ [Asn(B-D-fucosil)-Asp-Trp-Phe-Dap-Leu]ciclo(2B-5B) } [composto di formula I) in cui fucosil ) e gli altri sostituenti sono come definiti nell'esempio 1]. ESEMPIO 47 cycle {[Asn (B-D-fucosyl) -Asp-Trp-Phe-Dap-Leu] cycle (2B-5B)} [compound of formula I) in which fucosyl) and the other substituents are as defined in Example 1]. EXAMPLE 47
ciclo{ [Nle-Asp-Trp-Phe-Dap-Asn (β-D-f ucosil)]ciclo(2fì-5fì)} [composto di formula I) in cui {[Nle-Asp-Trp-Phe-Dap-Asn (β-D-f ucosyl)] cycle (2fì-5fì)} [compound of formula I) where
fucosil) e gli altri sostituenti sono come definiti nell'esempio 3]. fucosil) and the other substituents are as defined in Example 3].
ATTIVITÀ» BIOLOGICA »BIOLOGICAL ACTIVITY
La capacità dei prodotti della presente invenzione di interagire con il recettore della neurochinina A (NKA) come agonisti o antagonisti è stata valutata in vitro usando una preparazione nella quale la risposta biologica prodotta da tachichinine e peptidi correlati è determinata esclusivamente dal recettore della NKA (recettore NK2)· Tale preparato è l'arteria polmonare di coniglio, dove le tachichinine producono una contrazione dose-dipendente (Rovero et al., Neuropeptides, 1989, 13, 263-270). La determinazione dell'attività dei peptidi in questa preparazione è stata effettuata utilizzando la NKA come agonista. I peptidi oggetto della presente domanda venivano aggiunti al preparato in concentrazioni crescenti e la loro attività valutata come pKg (antilogaritmo della costante di dissociazione), come descritto in Jenkinson et al., TiPS, 12, 53-56, 1991. Ad esempio il composto 2 ha mostrato una ρΚβ = 8.67. La capacità dei prodotti della presente invenzione di interagire con il recettore della NKA come agonisti o antagonisti è stata valutata in vivo come capacità di inibire, dopo somministrazione endovenosa, le contrazioni della vescica urinaria nel ratto anestetizzato indotte dall1agonista [fiAla ] NKA (4-10), come descritto in Maggi et al., J. Pharmacol. Exp. Ther., 1991, 257, 1172. L'agonista è stato somministrato, prima e dopo la somministrazione del composto in esame, a intervalli di 20-30 min in modo da poter verificare, oltre la sua potenza, anche la durata d'azione del farmaco. Ad esempio il composto 1, alla dose di 10 nmol/kg i.v., produce un effetto inibitorio del 50-70%, valutato a vari tempi. L'effetto perdura per un tempo superiore alle 3 ore. The ability of the products of the present invention to interact with the neurokinin A (NKA) receptor as agonists or antagonists was evaluated in vitro using a preparation in which the biological response produced by tachykinins and related peptides is determined exclusively by the NKA receptor (receptor NK2) · This preparation is the rabbit pulmonary artery, where the tachykinins produce a dose-dependent contraction (Rovero et al., Neuropeptides, 1989, 13, 263-270). The determination of the peptide activity in this preparation was carried out using NKA as an agonist. The peptides object of the present application were added to the preparation in increasing concentrations and their activity evaluated as pKg (antilogarithm of the dissociation constant), as described in Jenkinson et al., TiPS, 12, 53-56, 1991. For example the compound 2 showed a ρΚβ = 8.67. The ability of the products of the present invention to interact with the NKA receptor as agonists or antagonists was evaluated in vivo as the ability to inhibit, after intravenous administration, the contractions of the urinary bladder in the anesthetized rat induced by the agonist [fiAla] NKA (4-10 ), as described in Maggi et al., J. Pharmacol. Exp. Ther., 1991, 257, 1172. The agonist was administered, before and after the administration of the compound under examination, at intervals of 20-30 min in order to verify, in addition to its potency, also the duration of action of the drug. For example, compound 1, at a dose of 10 nmol / kg i.v., produces an inhibitory effect of 50-70%, evaluated at various times. The effect lasts for more than 3 hours.
ABBREVIAZIONI: ABBREVIATIONS:
-L-asparagina -L-asparagine
glucopiranosil)-L-asparagina glucopyranosyl) -L-asparagine
^ ^
β-D-glucopiranosil)Na-(fluoren-9-ilmetossicarbonil)-L-asparagina pentafluorofenil estere β-D-glucopyranosyl) Na- (fluoren-9-ylmethoxycarbonyl) -L-asparagine pentafluorophenyl ester
-asparagina -asparagine
glucopiranosil)L-asparagina glucopyranosyl) L-asparagine
^ ^
β-D-glucopiranosil)Na-(fluoren-9-ilmetossicarbonil)-L-serina pentafluorofenil estere β-D-glucopyranosyl) Na- (fluoren-9-ylmethoxycarbonyl) -L-serine pentafluorophenyl ester
Claims (14)
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IL11739596A IL117395A (en) | 1995-03-13 | 1996-03-07 | Bicyclic compounds containing at least one hydrophilic group their preparation and use in pharmaceutical compositions as tachykinin antagonists |
EE9700230A EE03618B1 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinin antagonists, their preparation and use in a pharmaceutical composition |
CA002215372A CA2215372C (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical composition |
NZ303982A NZ303982A (en) | 1995-03-13 | 1996-03-11 | Bicyclic peptide compounds and their use as tachykinin antagonists |
AT96907421T ATE198481T1 (en) | 1995-03-13 | 1996-03-11 | BIZYCLIC TACHYKININ ANTAGONISTS, THEIR PREPARATION AND THEIR USE IN PHARMACEUTICAL COMPOSITIONS |
CNB961937629A CN1189477C (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinins antagonists, preparation thereof and their use in autagonistes composition |
SI9630276T SI0815126T1 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical composition |
SK1212-97A SK281899B6 (en) | 1995-03-13 | 1996-03-11 | Bicyclic peptides, pharmaceutical composition containing them and their use |
UA97104990A UA48962C2 (en) | 1995-03-13 | 1996-03-11 | Bicyclic antagonists of tachykinins, pharmaceutical composition and method of treatment |
EA199700223A EA000697B1 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical composition |
PCT/EP1996/001028 WO1996028467A1 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical composition |
RO97-01700A RO118297B1 (en) | 1995-03-13 | 1996-03-11 | Bi-cyclic peptides and pharmaceutical composition cotainig the same |
HU9801835A HU222051B1 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical composition |
DK96907421T DK0815126T3 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinin antagonists, their preparation and their use in pharmaceutical compositions |
BR9607348A BR9607348A (en) | 1995-03-13 | 1996-03-11 | Bicyclic compounds pharmaceutical compositions and processes for the treatment of arthritis asthma inflammations tumor growth gastrointestinal hypermotility huntigton's disease neuritis neuralgia hemicrania hypertension urticaria urinary incotinence symptoms of flu and cold carcinoid syndrome |
CZ19972862A CZ287372B6 (en) | 1995-03-13 | 1996-03-11 | Bicyclic peptides, their use and pharmaceutical preparation containing thereof |
ES96907421T ES2155187T3 (en) | 1995-03-13 | 1996-03-11 | BICYCLE ANTAGONISTS OF TAQUICINAS, PREPARATION OF THESE ANTAGONISTS AND ITS USE IN PHARMACEUTICAL COMPOUNDS. |
DE69611438T DE69611438T2 (en) | 1995-03-13 | 1996-03-11 | BIZYCLIC TACHYKININ ANTAGONISTS, THEIR PRODUCTION AND THEIR USE IN PHARMACEUTICAL COMPOSITIONS |
JP52726796A JP4618821B2 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinin antagonists, their preparation and their use in pharmaceutical compositions |
EP96907421A EP0815126B1 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical composition |
PL96322105A PL184147B1 (en) | 1995-03-13 | 1996-03-11 | Antagonists of tachokinins, method of obtaining them and using them in pharmaceutic compositions |
PT96907421T PT815126E (en) | 1995-03-13 | 1996-03-11 | BICYCLING ANTAGONISTS OF TAQUIQUININS PREPARATION OF THESE AND ITS USE OF PHARMACEUTICAL COMPOSITION |
MX9706927A MX9706927A (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical composition. |
AU51059/96A AU696528B2 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical composition |
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KR1019970706419A KR100405009B1 (en) | 1995-03-13 | 1996-03-11 | Bicyclic tachykinin antagonists, their use in medicaments and their use in pharmaceutical compositions |
ZA9601983A ZA961983B (en) | 1995-03-13 | 1996-03-12 | Bicyclic compounds, preparation thereof and use in pharmaceutical compositions. |
HR960117A HRP960117B1 (en) | 1995-03-13 | 1996-03-13 | Bicyclic compounds, their preparation and use in pharmaceutical preparations |
TW085103008A TW565572B (en) | 1995-03-13 | 1996-03-13 | Bicyclic compounds, preparation thereof and use in pharmaceutical compositions |
BG101849A BG63208B1 (en) | 1995-03-13 | 1997-08-22 | Bicyclic tachyquinine antagonists, their preparation and use in pharmaceutical compositions |
NO19974057A NO319290B1 (en) | 1995-03-13 | 1997-09-03 | Bicyclic compounds, pharmaceutical compositions containing them and the use of the compound for the preparation of a drug. |
US08/929,215 US6150325A (en) | 1995-03-13 | 1997-09-09 | Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical compositions |
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AU (1) | AU696528B2 (en) |
BG (1) | BG63208B1 (en) |
BR (1) | BR9607348A (en) |
CZ (1) | CZ287372B6 (en) |
DE (1) | DE69611438T2 (en) |
DK (1) | DK0815126T3 (en) |
EA (1) | EA000697B1 (en) |
EE (1) | EE03618B1 (en) |
ES (1) | ES2155187T3 (en) |
GE (1) | GEP20002271B (en) |
GR (1) | GR3035676T3 (en) |
HR (1) | HRP960117B1 (en) |
HU (1) | HU222051B1 (en) |
IL (1) | IL117395A (en) |
IT (1) | IT1277835B1 (en) |
MX (1) | MX9706927A (en) |
NO (1) | NO319290B1 (en) |
NZ (1) | NZ303982A (en) |
PL (1) | PL184147B1 (en) |
PT (1) | PT815126E (en) |
RO (1) | RO118297B1 (en) |
SK (1) | SK281899B6 (en) |
TW (1) | TW565572B (en) |
UA (1) | UA48962C2 (en) |
WO (1) | WO1996028467A1 (en) |
ZA (1) | ZA961983B (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6017705A (en) * | 1995-03-14 | 2000-01-25 | Ludwig Institute For Cancer Research | Isolated nucleic acid molecules which are members of the MAGE-B family and uses thereof |
IT1291776B1 (en) * | 1997-02-07 | 1999-01-21 | Menarini Ricerche Spa | MONOCYCLIC COMPOUNDS WITH FOUR BIFUNCTIONAL RESIDUES, HAVING NK-2 ANTAGONIST ACTION |
IT1304888B1 (en) * | 1998-08-05 | 2001-04-05 | Menarini Ricerche Spa | MONOCYCLIC ACTION COMPOUNDS NK-2 ANTAGONIST AND FORMULATIONS THAT CONTAIN |
CA2412355A1 (en) * | 2000-06-12 | 2001-12-20 | University Of Rochester | Method of treating symptoms of hormonal variation, including hot flashes, using tachykinin receptor antagonist |
EP1297826A1 (en) * | 2001-09-27 | 2003-04-02 | Menarini Ricerche S.p.A. | Nasal pharmaceutical compositions containing a NK-2 antagonist |
ITFI20020239A1 (en) * | 2002-12-06 | 2004-06-07 | Menarini Ricerche Spa | PROCESS FOR THE PREPARATION OF BICYCLIC PEPTID COMPOUNDS. |
ITFI20040221A1 (en) * | 2004-10-27 | 2005-01-27 | Guidotti & C Spa | PHARMACEUTICAL COMPOSITIONS BASED ON NK2 ANTAGONISTS FOR PEDIATRIC USE |
ITRM20120331A1 (en) | 2012-07-12 | 2014-01-13 | Guidotti & C Spa Labor | LIQUID ORAL PEDIATRIC COMPOSITIONS CONTAINING NEPADUTANT. |
Family Cites Families (1)
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IT1262902B (en) * | 1992-04-15 | 1996-07-22 | Menarini Farma Ind | TRICYCLIC COMPOUNDS ANTAGONISTS OF TACHYCHININS, THEIR PREPARATION AND THEIR USE IN PHARMACEUTICAL COMPOSITIONS. |
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1995
- 1995-03-13 IT IT95FI000044A patent/IT1277835B1/en active IP Right Grant
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1996
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- 1996-03-11 EA EA199700223A patent/EA000697B1/en not_active IP Right Cessation
- 1996-03-11 HU HU9801835A patent/HU222051B1/en active IP Right Grant
- 1996-03-11 AT AT96907421T patent/ATE198481T1/en active
- 1996-03-11 JP JP52726796A patent/JP4618821B2/en not_active Expired - Lifetime
- 1996-03-11 NZ NZ303982A patent/NZ303982A/en not_active IP Right Cessation
- 1996-03-11 MX MX9706927A patent/MX9706927A/en unknown
- 1996-03-11 DK DK96907421T patent/DK0815126T3/en active
- 1996-03-11 WO PCT/EP1996/001028 patent/WO1996028467A1/en active IP Right Grant
- 1996-03-11 GE GEAP19963873A patent/GEP20002271B/en unknown
- 1996-03-11 SK SK1212-97A patent/SK281899B6/en not_active IP Right Cessation
- 1996-03-11 AU AU51059/96A patent/AU696528B2/en not_active Expired
- 1996-03-11 EP EP96907421A patent/EP0815126B1/en not_active Expired - Lifetime
- 1996-03-11 RO RO97-01700A patent/RO118297B1/en unknown
- 1996-03-11 UA UA97104990A patent/UA48962C2/en unknown
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- 1996-03-11 CZ CZ19972862A patent/CZ287372B6/en not_active IP Right Cessation
- 1996-03-11 PL PL96322105A patent/PL184147B1/en unknown
- 1996-03-11 EE EE9700230A patent/EE03618B1/en unknown
- 1996-03-11 ES ES96907421T patent/ES2155187T3/en not_active Expired - Lifetime
- 1996-03-11 KR KR1019970706419A patent/KR100405009B1/en not_active IP Right Cessation
- 1996-03-11 PT PT96907421T patent/PT815126E/en unknown
- 1996-03-11 CN CNB961937629A patent/CN1189477C/en not_active Expired - Lifetime
- 1996-03-11 BR BR9607348A patent/BR9607348A/en active IP Right Grant
- 1996-03-12 ZA ZA9601983A patent/ZA961983B/en unknown
- 1996-03-13 HR HR960117A patent/HRP960117B1/en not_active IP Right Cessation
- 1996-03-13 TW TW085103008A patent/TW565572B/en not_active IP Right Cessation
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1997
- 1997-08-22 BG BG101849A patent/BG63208B1/en unknown
- 1997-09-03 NO NO19974057A patent/NO319290B1/en not_active IP Right Cessation
- 1997-09-09 US US08/929,215 patent/US6150325A/en not_active Expired - Lifetime
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2001
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